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    Clinical Trial Results:
    Extension Study of Protocol ENB-006-09 Evaluating the Long-Term Safety and Efficacy of Asfotase Alfa (Human Recombinant Tissue-Nonspecific Alkaline Phosphatase Fusion Protein) in Children with Hypophosphatasia (HPP)

    Summary
    EudraCT number
    		 2017-003153-42
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    30 Jun 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Oct 2018
    First version publication date
    20 Oct 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ENB-008-10
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01203826
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Alexion Pharma GmbH
    Sponsor organisation address
    Giesshübelstrasse 30, Zurich, Switzerland, 8045
    Public contact
    European Clinical Trial Information, Alexion Europe SAS, +33 147100606, clinicaltrials.eu@alexion.com
    Scientific contact
    European Clinical Trial Information, Alexion Europe SAS, +33 147100606, clinicaltrials.eu@alexion.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000987-PIP01-10
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Jun 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Jun 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study is an extension study of Protocol ENB-006-09. The primary objectives of this study are to assess the long-term tolerability of subcutaneous (SC) asfotase alfa and to assess the proportion of asfotase alfa-treated patients showing radiographic change in rickets severity from the Baseline of Study ENB-006-09 relative to the End of Study (EOS) visit in Study ENB-008-10 using an ordinal Radiographic Global Impression of Change (RGI-C) scale score.
    Protection of trial subjects
    This study was designed, conducted, recorded, and reported in accordance with ethical principles that have their origin in the Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects, and are consistent with International Council on Harmonisation Good Clinical Practice guidelines and in accordance with applicable local, federal, and regulatory agency regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Apr 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    United States: 9
    Worldwide total number of subjects
    12
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    10
    Adolescents (12-17 years)
    2
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The main criteria for inclusion in Study ENB-006-09 were patients ages 5 to 12 years inclusive, with open growth plates at time of study entry and a documented diagnosis of HPP. To enter the extension, Study ENB-008-10, patients had to successfully complete Study ENB-006-09 and provide consent.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 2 mg/kg Asfotase Alfa
    Arm description
    		 Upon initial enrollment in Study ENB-006-09, patients were randomized to receive 2 milligram (mg)/kilogram (kg) asfotase alfa 3 times weekly. In study ENB-008-010 (extension study of ENB-006-09), patients received a starting dose of 3 mg/kg/week asfotase alfa. The dose in the extension study was subsequently increased per study-wide dose adjustment to a total dose of 6 mg/kg/week. Results are shown by the patient's dose group assignment from Study ENB-006-09. Results presented are for Study ENB-008-10 only.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Asfotase Alfa
    Investigational medicinal product code
    Other name
    human recombinant tissue nonspecific alkaline phosphatase fusion protein
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    In this extension study, all patients initially received 3 mg/kg/week of asfotase alfa administered by SC injection. Following analysis of results from Study ENB-006-09, the dosage was modified such that patients received 6 mg/kg/week, administered as 2 mg/kg 3 times per week or as 1 mg/kg 6 times per week at the discretion of the Investigator. Patients received treatment with asfotase alfa for at least 72 months or until the product became commercially available.

    Arm title
    		 3 mg/kg Asfotase Alfa
    Arm description
    		 Upon initial enrollment in Study ENB-006-09, patients were randomized to receive 3 mg/kg asfotase alfa 3 times weekly. In study ENB-008-010 (extension study of ENB-006-09), patients received a starting dose of 3 mg/kg/week asfotase alfa. The dose in the extension study was subsequently increased per study-wide dose adjustment to a total dose of 6 mg/kg/week. Results are shown by the patient's dose group assignment from Study ENB-006-09. Results presented are for Study ENB-008-10 only.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Asfotase Alfa
    Investigational medicinal product code
    Other name
    human recombinant tissue nonspecific alkaline phosphatase fusion protein
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    In this extension study, all patients initially received 3 mg/kg/week of asfotase alfa administered by SC injection. Following analysis of results from Study ENB-006-09, the dosage was modified such that patients received 6 mg/kg/week, administered as 2 mg/kg 3 times per week or as 1 mg/kg 6 times per week at the discretion of the Investigator. Patients received treatment with asfotase alfa for at least 72 months or until the product became commercially available.

    Number of subjects in period 1
    		2 mg/kg Asfotase Alfa 3 mg/kg Asfotase Alfa
    Started
    6
    6
    Completed
    6
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    2 mg/kg Asfotase Alfa
    Reporting group description
    		 Upon initial enrollment in Study ENB-006-09, patients were randomized to receive 2 milligram (mg)/kilogram (kg) asfotase alfa 3 times weekly. In study ENB-008-010 (extension study of ENB-006-09), patients received a starting dose of 3 mg/kg/week asfotase alfa. The dose in the extension study was subsequently increased per study-wide dose adjustment to a total dose of 6 mg/kg/week. Results are shown by the patient's dose group assignment from Study ENB-006-09. Results presented are for Study ENB-008-10 only.

    Reporting group title
    3 mg/kg Asfotase Alfa
    Reporting group description
    		 Upon initial enrollment in Study ENB-006-09, patients were randomized to receive 3 mg/kg asfotase alfa 3 times weekly. In study ENB-008-010 (extension study of ENB-006-09), patients received a starting dose of 3 mg/kg/week asfotase alfa. The dose in the extension study was subsequently increased per study-wide dose adjustment to a total dose of 6 mg/kg/week. Results are shown by the patient's dose group assignment from Study ENB-006-09. Results presented are for Study ENB-008-10 only.

    Reporting group values
    		 2 mg/kg Asfotase Alfa 3 mg/kg Asfotase Alfa Total
    Number of subjects
    		 6 6 12
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 5 5 10
        Adolescents (12-17 years)
    		 1 1 2
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (standard deviation)
    		 8.4 ± 2.21 9.0 ± 2.51 -
    Gender categorical
    Units: Subjects
        Female
    		 1 1 2
        Male
    		 5 5 10
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 6 6 12
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 1 0 1
        Not Hispanic or Latino
    		 5 6 11
        Unknown or Not Reported
    		 0 0 0
    Region of Enrollment
    Units: Subjects
        Canada
    		 2 1 3
        United States
    		 4 5 9
    Hypophosphatasia Phenotype
    Units: Subjects
        Infantile (< 6 months)
    		 3 1 4
        Juvenile (≥ 6 months to < 18 yrs)
    		 3 5 8
    Tanner Staging
    Measure Description: n %; Tanner Stage 1 = Prepubertal children
    Units: Subjects
        Tanner Stage 1
    		 6 6 12
    Age at Onset of Hypophosphatasia Symptoms
    Units: Months
        arithmetic mean (standard deviation)
    		 10.8 ± 8.66 11.5 ± 5.54 -
    Subject analysis sets

    Subject analysis set title
    Asfotase Alfa Combined
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients that received treatment with asfotase alfa in Study ENB-008-10.

    Subject analysis sets values
    		 Asfotase Alfa Combined
    Number of subjects
    12
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    10
        Adolescents (12-17 years)
    2
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        median (standard deviation)
    8.7 ± 2.27
    Gender categorical
    Units: Subjects
        Female
    2
        Male
    10
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0
        Asian
    0
        Native Hawaiian or Other Pacific Islander
    0
        Black or African American
    0
        White
    12
        More than one race
    0
        Unknown or Not Reported
    0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    1
        Not Hispanic or Latino
    11
        Unknown or Not Reported
    0
    Region of Enrollment
    Units: Subjects
        Canada
    3
        United States
    9
    Hypophosphatasia Phenotype
    Units: Subjects
        Infantile (< 6 months)
    4
        Juvenile (≥ 6 months to < 18 yrs)
    8
    Tanner Staging
    Measure Description: n %; Tanner Stage 1 = Prepubertal children
    Units: Subjects
        Tanner Stage 1
    12
    Age at Onset of Hypophosphatasia Symptoms
    Units: Months
        arithmetic mean (standard deviation)
    11.2 ± 6.94

    End points

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    End points reporting groups
    Reporting group title
    2 mg/kg Asfotase Alfa
    Reporting group description
    		 Upon initial enrollment in Study ENB-006-09, patients were randomized to receive 2 milligram (mg)/kilogram (kg) asfotase alfa 3 times weekly. In study ENB-008-010 (extension study of ENB-006-09), patients received a starting dose of 3 mg/kg/week asfotase alfa. The dose in the extension study was subsequently increased per study-wide dose adjustment to a total dose of 6 mg/kg/week. Results are shown by the patient's dose group assignment from Study ENB-006-09. Results presented are for Study ENB-008-10 only.

    Reporting group title
    3 mg/kg Asfotase Alfa
    Reporting group description
    		 Upon initial enrollment in Study ENB-006-09, patients were randomized to receive 3 mg/kg asfotase alfa 3 times weekly. In study ENB-008-010 (extension study of ENB-006-09), patients received a starting dose of 3 mg/kg/week asfotase alfa. The dose in the extension study was subsequently increased per study-wide dose adjustment to a total dose of 6 mg/kg/week. Results are shown by the patient's dose group assignment from Study ENB-006-09. Results presented are for Study ENB-008-10 only.

    Subject analysis set title
    Asfotase Alfa Combined
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients that received treatment with asfotase alfa in Study ENB-008-10.

    Primary: Skeletal Radiograph Evaluation Using a Qualitative RGI-C Scale Compared to Baseline (Pre-treatment) in Study ENB-006-09

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    End point title
    		 Skeletal Radiograph Evaluation Using a Qualitative RGI-C Scale Compared to Baseline (Pre-treatment) in Study ENB-006-09 [1]
    End point description
    Evaluation of radiographic change in rickets severity (assessed by skeletal radiographs of hands/wrists and knees) from Baseline of Study ENB-006-09 (EudraCT number 2015-001128-52, NCT00952484) to EOS visit in Study ENB-008-10 using an ordinal RGI-C scale score. The RGI-C is a 7-point rating scale ranging from -3 (indicates severe worsening of HPP associated rickets) to +3 (indicates complete or near complete healing of HPP associated rickets). The timepoints are pre-treatment (Baseline from Study ENB-006-09) to the last radiographic assessment in Study ENB-008-10, which represents at least 72 months of treatment. The RGI-C score represents evaluations of skeletal X-rays at each post-treatment timepoint in Study ENB-008-10 compared with pre-treatment X-rays from Study ENB-006-09, using an ordinal scale. Therefore, no Baseline data for RGI-C are available. A Wilcoxon signed-rank test was used to test if the change in rickets severity was different from 0; the resulting p-value=0.0005.
    End point type
    Primary
    End point timeframe
    At least 72 months of treatment with asfotase alfa
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to the limitations of the EudraCT database, the method used for the calculation of the p-value and the p-value were reported in the endpoint description.
    End point values
    		 Asfotase Alfa Combined
    Number of subjects analysed
    12
    Units: Units on a Scale
        median (full range (min-max))
    2.83 (2.0 to 3.0)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events are events starting on or after the day of first dose of asfotase alfa and recorded in Study ENB-008-10 (at least 66 months of treatment in Study ENB-008-10).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    2 mg/kg Asfotase Alfa
    Reporting group description
    		 Upon initial enrollment in Study ENB-006-09, patients were randomized to receive 2 mg/kg asfotase alfa 3 times weekly. In study ENB-008-010 (extension study of ENB-006- 09), patients received a starting dose of 3 mg/kg/week asfotase alfa. The dose in the extension study was subsequently increased per study-wide dose adjustment to a total dose of 6 mg/kg/week. Results are shown by the patient's dose group assignment from Study ENB-006-09. Results presented are for Study ENB-008-10 only.

    Reporting group title
    3 mg/kg Asfotase Alfa
    Reporting group description
    		 Upon initial enrollment in Study ENB-006-09, patients were randomized to receive 3 mg/kg asfotase alfa 3 times weekly. In study ENB-008-010 (extension study of ENB-006- 09), patients received a starting dose of 3 mg/kg/week asfotase alfa. The dose in the extension study was subsequently increased per study-wide dose adjustment to a total dose of 6 mg/kg/week. Results are shown by the patient's dose group assignment from Study ENB-006-09. Results presented are for Study ENB-008-10 only.

    Reporting group title
    Asfotase Alfa Combined
    Reporting group description
    		 All patients that received treatment with asfotase alfa in Study ENB-008-10.

    Serious adverse events
    		 2 mg/kg Asfotase Alfa 3 mg/kg Asfotase Alfa Asfotase Alfa Combined
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 2 mg/kg Asfotase Alfa 3 mg/kg Asfotase Alfa Asfotase Alfa Combined
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    12 / 12 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemangioma
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Melanocytic naevus
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    3
    0
    3
    Skin papilloma
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    3 / 12 (25.00%)
         occurrences all number
    7
    1
    8
    General disorders and administration site conditions
    Discomfort
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Fatigue
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    3 / 12 (25.00%)
         occurrences all number
    2
    2
    4
    Gait disturbance
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 6 (50.00%)
    3 / 12 (25.00%)
         occurrences all number
    0
    3
    3
    Injection site atrophy
         subjects affected / exposed
    3 / 6 (50.00%)
    3 / 6 (50.00%)
    6 / 12 (50.00%)
         occurrences all number
    10
    8
    18
    Injection site discolouration
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    4 / 12 (33.33%)
         occurrences all number
    8
    8
    16
    Injection site erythema
         subjects affected / exposed
    4 / 6 (66.67%)
    6 / 6 (100.00%)
    10 / 12 (83.33%)
         occurrences all number
    18
    27
    45
    Injection site hypersensitivity
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Injection site hypertrophy
         subjects affected / exposed
    4 / 6 (66.67%)
    4 / 6 (66.67%)
    8 / 12 (66.67%)
         occurrences all number
    14
    13
    27
    Injection site induration
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Injection site macule
         subjects affected / exposed
    4 / 6 (66.67%)
    5 / 6 (83.33%)
    9 / 12 (75.00%)
         occurrences all number
    28
    31
    59
    Injection site pain
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    3 / 12 (25.00%)
         occurrences all number
    6
    2
    8
    Injection site papule
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Injection site pruritus
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    12
    0
    12
    Injection site reaction
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Injection site swelling
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    7
    7
    Injection site urticaria
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Pyrexia
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    3 / 12 (25.00%)
         occurrences all number
    2
    1
    3
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Seasonal allergy
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    7
    0
    7
    Reproductive system and breast disorders
    Balanitis
         subjects affected / exposed [1]
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Allergic cough
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Allergic sinusitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    2
    Cough
         subjects affected / exposed
    3 / 6 (50.00%)
    0 / 6 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    5
    0
    5
    Epistaxis
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 12 (16.67%)
         occurrences all number
    1
    1
    2
    Nasal congestion
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    2
    Oropharyngeal pain
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 12 (16.67%)
         occurrences all number
    1
    1
    2
    Rhinitis allergic
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 12 (16.67%)
         occurrences all number
    1
    1
    2
    Psychiatric disorders
    Acute stress disorder
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Anxiety
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    2
    2
    Attention deficit/hyperactivity disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Initial insomnia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Investigations
    Blood 25-hydroxycholecalciferol decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Injury, poisoning and procedural complications
    Accidental exposure
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    2
    2
    Ankle fracture
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Arthropod bite
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    2
    0
    2
    Arthropod sting
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Burns second degree
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Contusion
         subjects affected / exposed
    3 / 6 (50.00%)
    0 / 6 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    3
    0
    3
    Drug administration error
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Joint injury
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Joint sprain
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    3 / 12 (25.00%)
         occurrences all number
    1
    2
    3
    Limb injury
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 12 (16.67%)
         occurrences all number
    1
    1
    2
    Muscle strain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Periorbital haematoma
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Post-traumatic pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Procedural pain
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    3
    0
    3
    Radius fracture
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Testicular injury
         subjects affected / exposed [2]
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    1
    Congenital, familial and genetic disorders
    Phimosis
         subjects affected / exposed [3]
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Headache
         subjects affected / exposed
    3 / 6 (50.00%)
    3 / 6 (50.00%)
    6 / 12 (50.00%)
         occurrences all number
    15
    4
    19
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Middle ear inflammation
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Eye disorders
    Conjunctival deposit
         subjects affected / exposed
    3 / 6 (50.00%)
    3 / 6 (50.00%)
    6 / 12 (50.00%)
         occurrences all number
    5
    3
    8
    Conjunctivitis
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 12 (16.67%)
         occurrences all number
    1
    1
    2
    Conjunctivitis allergic
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Corneal deposits
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Optic atrophy
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Optic disc drusen
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Retinal vascular disorder
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Gastrointestinal disorders
    Dental discomfort
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    3
    0
    3
    Diarrhoea
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    2
    0
    2
    Food poisoning
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    2 / 12 (16.67%)
         occurrences all number
    0
    3
    3
    Oral pain
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 12 (16.67%)
         occurrences all number
    3
    1
    4
    Tooth crowding
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Toothache
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    2 / 12 (16.67%)
         occurrences all number
    0
    2
    2
    Dermatitis allergic
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Eczema
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    2 / 12 (16.67%)
         occurrences all number
    0
    2
    2
    Hair colour changes
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Ingrowing nail
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    2 / 12 (16.67%)
         occurrences all number
    0
    2
    2
    Skin discolouration
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Urticaria
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    2 / 12 (16.67%)
         occurrences all number
    0
    6
    6
    Nephrocalcinosis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Endocrine disorders
    Growth hormone deficiency
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 6 (66.67%)
    1 / 6 (16.67%)
    5 / 12 (41.67%)
         occurrences all number
    6
    2
    8
    Epiphyses premature fusion
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    2
    Joint hyperextension
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Joint swelling
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 12 (16.67%)
         occurrences all number
    1
    2
    3
    Muscular weakness
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    2 / 12 (16.67%)
         occurrences all number
    0
    2
    2
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    2
    Myalgia
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    3 / 12 (25.00%)
         occurrences all number
    3
    1
    4
    Neck pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Pain in extremity
         subjects affected / exposed
    3 / 6 (50.00%)
    0 / 6 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    6
    0
    6
    Tendonitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 12 (16.67%)
         occurrences all number
    1
    2
    3
    Ear infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Enterobiasis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Gastroenteritis
         subjects affected / exposed
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    5 / 12 (41.67%)
         occurrences all number
    3
    5
    8
    Gastroenteritis viral
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    2
    0
    2
    Influenza
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    2
    Otitis media
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Pharyngitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    2
    2
    Pneumonia
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 6 (50.00%)
    3 / 12 (25.00%)
         occurrences all number
    0
    3
    3
    Sinusitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    2
    Staphylococcal skin infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    2
    2
    Tinea cruris
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Tonsillitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 6 (83.33%)
    4 / 6 (66.67%)
    9 / 12 (75.00%)
         occurrences all number
    24
    20
    44
    Viral infection
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 12 (16.67%)
         occurrences all number
    1
    2
    3
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This adverse event only affects male patients; therefore, only male patients were reported for this event.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This adverse event only affects male patients; therefore, only male patients were reported for this event.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This adverse event only affects male patients; therefore, only male patients were reported for this event.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 May 2010
    • Language was added to the description of medical history assessment to collect detailed historical information in the absence of treatment for consenting patients through retrospective medical records review • Language was added to include summarization and analysis of collected medical history • Injection site reactions were included in preliminary safety-related findings for precursor Study ENB-006-09
    05 Aug 2010
    • Several functional assessments were added to the Month 3 and 9 study visits to monitor changes in motor function and other measures, including 6-Minute Walk Test (6MWT), shuttle run and standing long jump subtest of the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition (BOT-2), hand-held dynamometry (HHD), and pain portion of the Child Health Assessment Questionnaire (CHAQ) • Language was removed to reflect that adjudication of differing RGI-C scores was not required for statistical analysis of the primary efficacy endpoint for the study
    13 Oct 2010
    • Language was added to clarify the primary efficacy endpoint • A single transiliac crest bone biopsy at Month 9 or 12 was added to examination criteria to assist in evaluating the long-term effects of asfotase alfa treatment on osteomalacia when compared with results from the precursor study ENB-006-09 • Additional testing added at Months 3 and 9 for BOT-2 subtests, HHD, and CHAQ disability and pain
    01 Feb 2011
    • The study methodology and statistical analyses were updated to reflect that the study was extended from 12 to at least 42 months • The primary objectives of the study were updated to emphasize the long-term tolerability of SC asfotase alfa and the long-term efficacy of asfotase alfa in treating rickets in children with HPP • Secondary and exploratory study objectives were updated to reflect that the study will now focus on the pharmacokinetics of SC asfotase alfa. • The transiliac crest bone biopsy, panorex radiographs, and pulmonary function tests were eliminated. • Examination criteria, including body mass index, arm span, dual energy X-ray absorptiometry, disability, and pain, were changed from exploratory to secondary objectives. • The dose was changed from 3 to 6 mg/kg/week to reflect the interim study results for Study ENB-006-09. • The number of study sites was decreased from 5 to 2 to reflect that only 2 sites had patients enrolled, and the number of patients planned for this study was updated based on the number (12) that completed the initial study. • The dose adjustment language was updated to reflect the fact that safety issues can arise at any time, and it is in the patients’ best interest to have flexibility to adjust the dose at any time during the study with input from the Investigator. • The Efficacy Evaluation section was updated to reflect current examination criteria. • Urine calcium:creatinine ratios were moved from safety measures to pharmacodynamic assessments to align with other recent protocols in the program. • X-ray of the lateral skull was removed due to being considered unnecessary as a safety measurement in this population.
    30 Jul 2014
    • Extended the study duration to regulatory approval and commercial availability of asfotase alfa or at least 72 months. • Added a requirement for pregnancy testing, as patients in the study were reaching childbearing potential. • Updated wording regarding dose adjustments for efficacy or safety reasons. • Full ophthalmology examinations (including funduscopy) were added to better characterize potential ectopic calcifications. • Changes to Data Monitoring Committee (DMC) operations (endorsed by the DMC) were made based on a new DMC charter (dated 10 Jan 2013) and Sponsor discussions on DMC stopping rules; ad hoc review and stopping rules are no longer required; however, the DMC was to be notified immediately. • Changed testing requirements for injection-associated reactions.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27699270
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